“Nucleic acid vaccine” is a general term reflecting technologies which are used to direct the synthesis of target (vaccine) proteins in cells of the recipient, via administration of either DNA (plasmids) or self-replicating, sub-genomic viral nucleic acids (viral replicons).
Nucleic acid vaccines, and DNA vaccines in particular, in which plasmid DNAs encoding protein antigens are administered rather than the proteins themselves, have become the focus of intense research worldwide since the observation that naked DNA could induce antigen synthesis in vivo leading to the induction of immune responses (Wolff et al, 1990). Two major potential advantages in the use of nucleic acid vaccines are (a) the presentation of native epitopes to the immune system after expression of the protein in cells of the recipient, and (b) the chemical homogeneity, ease of preparation, and stability of nucleic acids, which will be of particular utility for combined vaccines and for use in the absence of the cold chain required for conventional vaccines.
The great majority of effective “traditional” vaccines are directed at acute, self-limiting infections and elicit an immune response which mimics that associated with recovery from, and immunity to, the corresponding infection. That is, they rely on the normal immune response to antigens from the infectious agent, presented in their native form(s). Nucleic acid vaccines have a strategic advantage in such systems. In the past this has generally been achieved by the use of either (i) live, attenuated vaccine organisms (e.g., Sabin polio vaccines); (ii) wild-type organisms (or bacterial toxins) which are subsequently inactivated (e.g., Salk polio vaccines), or (iii) manufacture of native antigens using recombinant DNA technology (eg subunit hepatitis B vaccines). In this context, DNA vaccines have the great advantage that the target antigens are synthesised in a native form within cells of the recipient. This is also true of viral replicon-based delivery systems (for example, the Kunjin replicon system (Khromykh, et al. 1997; Varnavski, et al. 1999; Varnavski, et al. 2000). However, antibody responses to DNA vaccines encoded antigens are frequently low or undetectable.
Much less progress has been made in the development of preventative and therapeutic vaccines against infections where the normal immune response fails to clear the infection. For agents such as HCV and the Human Immunodeficiency Virus (HIV) where failure to clear infection is the norm, vaccines which are able to induce the normal immune response to relevant antigens may have little utility. This is also true of tumour-specific antigens which are usually seen as “self” and thus the normal immune response is one of tolerance. Despite their many potential advantages, standard DNA or replicon vaccines may be ineffective in such cases, precisely because they encode antigens in their native forms.
A variety of methods have been used to modulate immune responses to DNA vaccines, including (i) co-delivery of cytokines or cytokine-encoding plasmids; (ii) the immunostimulatory role of CpG dinucleotides commonly found in bacterial (and plasmid) DNAs (Hemmi et al, 2000); and (iii) prime-boost protocols, utilising DNA vaccines together with poxvirus vectors.
Existing strategies for antigen targeting include the use of (a) ubiquitin fusions (ubiquitin-A76 or -G76-K) to target proteins for polyubiquitination, rapid intracellular degradation in proteasomes and efficient MHC-I presentation; (b) fusion to lysosome-associated membrane protein 1 (LAMP-1) to target the MHC-II pathway; (c) fusion to the adenovirus E3 leader sequence to target the epitope to the endoplasmic reticulum (ER); and (d) fusion to CTLA4 to target the epitope for secretion and uptake by professional antigen presenting cells (APCs).
However, the efficacy of many DNA vaccines has been poor (Gurunathan S et al, 2000) and there is a need for the development of improved technologies and molecules to modulate the immune response to proteins expressed by DNA vaccines leading to recovery or protection.